rs2076349

chr1-209626885-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000228.3(LAMB3):c.1579G>A(p.Val527Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0695 in 1,613,446 control chromosomes in the GnomAD database, including 14,383 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 2724 hom., cov: 33)

Exomes 𝑓: 0.063 ( 11659 hom. )

Consequence

LAMB3
NM_000228.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.601

Variant links:

Genes affected

LAMB3 (HGNC:6490): (laminin subunit beta 3) The product encoded by this gene is a laminin that belongs to a family of basement membrane proteins. This protein is a beta subunit laminin, which together with an alpha and a gamma subunit, forms laminin-5. Mutations in this gene cause epidermolysis bullosa junctional Herlitz type, and generalized atrophic benign epidermolysis bullosa, diseases that are characterized by blistering of the skin. Multiple alternatively spliced transcript variants that encode the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

LAMB3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.3354112E-5).

BP6

Variant 1-209626885-C-T is Benign according to our data. Variant chr1-209626885-C-T is described in ClinVar as [Benign]. Clinvar id is 255586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMB3	NM_000228.3 linkuse as main transcript	c.1579G>A	p.Val527Met	missense_variant	13/23	ENST00000356082.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
LAMB3	ENST00000356082.9 linkuse as main transcript	c.1579G>A	p.Val527Met	missense_variant	13/23	1	NM_000228.3	P1
LAMB3	ENST00000367030.7 linkuse as main transcript	c.1579G>A	p.Val527Met	missense_variant	13/23	1		P1
LAMB3	ENST00000391911.5 linkuse as main transcript	c.1579G>A	p.Val527Met	missense_variant	12/22	1		P1

Frequencies

GnomAD3 genomes

AF:

0.130

AC:

19792

AN:

152182

Hom.:

2710

Cov.:

show subpopulations

Gnomad AFR

AF:

0.267

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.184

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.572

Gnomad SAS

AF:

0.118

Gnomad FIN

AF:

0.0165

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0277

Gnomad OTH

AF:

0.117

GnomAD3 exomes

AF:

0.132

AC:

32973

AN:

250462

Hom.:

5717

AF XY:

0.118

AC XY:

15976

AN XY:

135570

show subpopulations

Gnomad AFR exome

AF:

0.274

Gnomad AMR exome

AF:

0.300

Gnomad ASJ exome

AF:

0.0196

Gnomad EAS exome

AF:

0.581

Gnomad SAS exome

AF:

0.108

Gnomad FIN exome

AF:

0.0203

Gnomad NFE exome

AF:

0.0271

Gnomad OTH exome

AF:

0.0888

GnomAD4 exome

AF:

0.0632

AC:

92355

AN:

1461146

Hom.:

11659

Cov.:

AF XY:

0.0627

AC XY:

45604

AN XY:

726892

show subpopulations

Gnomad4 AFR exome

AF:

0.285

Gnomad4 AMR exome

AF:

0.289

Gnomad4 ASJ exome

AF:

0.0183

Gnomad4 EAS exome

AF:

0.577

Gnomad4 SAS exome

AF:

0.110

Gnomad4 FIN exome

AF:

0.0208

Gnomad4 NFE exome

AF:

0.0271

Gnomad4 OTH exome

AF:

0.0888

GnomAD4 genome

AF:

0.130

AC:

19855

AN:

152300

Hom.:

2724

Cov.:

AF XY:

0.132

AC XY:

9830

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.267

Gnomad4 AMR

AF:

0.185

Gnomad4 ASJ

AF:

0.0167

Gnomad4 EAS

AF:

0.572

Gnomad4 SAS

AF:

0.118

Gnomad4 FIN

AF:

0.0165

Gnomad4 NFE

AF:

0.0277

Gnomad4 OTH

AF:

0.120

Alfa

AF:

0.0641

Hom.:

2522

Bravo

AF:

0.155

TwinsUK

AF:

0.0213

AC:

ALSPAC

AF:

0.0291

AC:

112

ESP6500AA

AF:

0.254

AC:

1119

ESP6500EA

AF:

0.0271

AC:

233

ExAC

AF:

0.125

AC:

15136

Asia WGS

AF:

0.308

AC:

1073

AN:

3478

EpiCase

AF:

0.0297

EpiControl

AF:

0.0263

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Junctional epidermolysis bullosa, non-Herlitz type

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 08, 2021

- -

Amelogenesis imperfecta type 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 08, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Junctional epidermolysis bullosa gravis of Herlitz

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 08, 2021

- -

Junctional epidermolysis bullosa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

Cadd

Benign

9.7

Dann

Uncertain

0.98

DEOGEN2

Benign

0.060

T;T;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.056

MetaRNN

Benign

0.000013

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.0

M;M;M

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.45

N;N;N

REVEL

Benign

0.035

Sift

Benign

0.068

T;T;T

Sift4G

Benign

0.074

T;T;T

Polyphen

0.60

P;P;P

Vest4

0.023

MPC

0.13

ClinPred

0.0076

GERP RS

-2.5

Varity_R

0.074

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over